Some small interfering RNAs (siRNAs) can cause a variety of nonspecific side effects, including the stimulation of interferon and cytokine production, global shutdown of protein synthesis, nonspecific degradation of mRNAs, and off-target effects resulting in nonspecific reduction of expression of genes (Robbins et al., 2009). For many siRNA applications, specific gene silencing is preferred, and activation of innate immunity in a subject following administration of siRNA is considered an undesirable side effect.
In cancer therapy, however, these immunostimulatory siRNAs, or “isRNAs”, can be used as potent immunomodulatory agents, for activating beneficial effects including proliferation blockage, differentiation, and apoptosis that are desirable in cancer cells. Thus, the innate immune system can serve as an tumor suppressor (Shankaran et al., 2001; Bui and Schreiber, 2007; Koebel et al., 2007), and immunostimulating agents can be used in antitumor therapy.
However, there remains a need for effective techniques that are capable of restricting isRNA activation of the innate immune response to tumor cells and not generally in non-tumor cells in a human or animal.